Project Summary/Abstract An ester of a beta blocker, esmolol, was introduced 30 years ago to facilitate the use of beta blockers in the acute care setting. IV beta blockers have a long half-life and this discouraged their use acutely. Esmolol, because of its short half-life became a very commercially successful agent, currently seeing increased clinical use. Anti-arrhythmic agents cause significant side effects and may cause severe arrhythmias. Sotalol is a drug often used to treat supraventricular arrhythmias, but its prolongation of the QT interval and the specter of life threatening arrhythmias such as Torsade de Pointe ventricular tachycardia limits its use. Having a sotalol like agent, but with a half-life of minutes would be clinically useful. If excessive QT prolongation is observed, or ventricular arrhythmias develop, the short acting agent could be stopped and it would quickly dissipate, enhancing patient safety. We have synthesized a sotalol conjurer with an ester linkage, which would be rapidly hydrolyzed in the blood by circulating esterase yielding a drug with a short half-life. The studies outlined in this initial grant would demonstrate anti-arrhythmic activities of the new agent, soestolol, in animal models of supraventricular and ventricular arrhythmias. We also plan to develop an assay for the drug based on our sotalol assay to verify that, indeed, the kinetic half-life is short. Additionally, by following QT effects, we will determine that the biologic half-life is equally short as the kinetic half-life. Soestolol, if it indeed is an effective anti-arrhythmic with a short half-life, will be a commercial success, as well as contributing significantly to patient care and safety.